Highly Active Antiretroviral Therapy (HAART), defined as the administration of three or more antiretroviral medications in combination, has significantly reduced the morbidity and mortality associated with HIV infection. Although there are currently 26 FDA approved drugs in six different mechanistic classes that are given in various HAART combinations, there is a growing need for new antiviral agents to address the critical issues of resistance and penetration into viral sanctuaries (commonly referred to as privileged compartments). Nucleoside analogues that inhibit the HIV encoded reverse transcriptase (RT) continue to be the cornerstone of antiviral therapy; however, one of the major problems in designing next generation nucleoside analogues with more favorable clinical profiles has been the failure of many of these analogues to be recognized and activated by phosphorylation by host kinases. Since the lack of phosphorylating activity generally occurs at the point of the first or second of the three phosphorylation steps required to convert a nucleoside analogue into a competitive, alternative substrate inhibitor of the RT, it may be possible to circumvent this problem by designing nucleotide diphosphate analogues. Additionally, permeability into privileged compartments may be partially responsible for the current inability of chemotherapy to totally clear a patient of HIV infection and the emergence of resistance. Two important privileged HIV compartments are the central nervous system (CNS) and the gut-associated lymphoid tissue (GALT). Our operating hypothesis is that it is possible to design a next generation antiretroviral drug as a nucleoside mono- or diphosphate scaffold with a more favorable resistance profile and achieve therapeutic concentrations of the activated (triphosphate) analogue in currently undertreated privileged compartments by conjugation with sphingolipid moieties.